Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis
Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis
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DOI：
10.1073/pnas.1208069109
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发表时间：
2012-09-25
影响因子：
11.1
通讯作者：
Riscoe, Michael K.
中科院分区：
文献类型：
--
作者：
Doggett, J. Stone;Nilsen, Aaron;Riscoe, Michael K.
弓形虫是一种广泛分布的原生动物病原体，可引起严重的眼部和中枢神经系统疾病。我们发现，类内皮素喹诺酮（ELQ）类化合物含有非常有效的T。弓形虫体外生长，对小鼠急性和潜伏弓形虫病有效。我们对50个ELQ进行了T.选择两种先导化合物ELQ-271和ELQ-316进行评价。ELQ-271和ELQ-316的体外IC 50值分别为0.1 nM和0.007 nM。ELQ-271和ELQ-316经口给予急性弓形虫病小鼠时，ED 50值分别为0.14 mg/kg和0.08 mg/kg。此外，ELQ-271和ELQ-316对T.在低剂量下，小鼠体内的弓形虫，在治疗16天后将囊肿负担减少76-88%。探讨ELQ抗T.我们证明endochin和ELQ-271抑制T.弓形虫细胞色素bc（1）复合物分别为8 nM和31 nM。我们还表明，ELQ-271抑制酿酒酵母细胞色素bc（1）复合物，并且蛋白质Q（i）位点的M221 Q氨基酸取代导致> 100倍的抗性。我们得出结论，ELQ-271和ELQ-316是口服生物可利用的药物，对急性和潜伏期弓形虫病有效，可能作为T.弓形虫细胞色素BC（1）复合物。
Toxoplasma gondii is a widely distributed protozoan pathogen that causes devastating ocular and central nervous system disease. We show that the endochin-like quinolone (ELQ) class of compounds contains extremely potent inhibitors of T. gondii growth in vitro and is effective against acute and latent toxoplasmosis in mice. We screened 50 ELQs against T. gondii and selected two lead compounds, ELQ-271 and ELQ-316, for evaluation. ELQ-271 and ELQ-316, have in vitro IC50 values of 0.1 nM and 0.007 nM, respectively. ELQ-271 and ELQ-316 have ED50 values of 0.14 mg/kg and 0.08 mg/kg when administered orally to mice with acute toxoplasmosis. Moreover, ELQ-271 and ELQ-316 are highly active against the cyst form of T. gondii in mice at low doses, reducing cyst burden by 76-88% after 16 d of treatment. To investigate the ELQ mechanism of action against T. gondii, we demonstrate that endochin and ELQ-271 inhibit cytochrome c reduction by the T. gondii cytochrome bc(1) complex at 8 nM and 31 nM, respectively. We also show that ELQ-271 inhibits the Saccharomyces cerevisiae cytochrome bc(1) complex, and an M221Q amino acid substitution in the Q(i) site of the protein leads to > 100-fold resistance. We conclude that ELQ-271 and ELQ-316 are orally bioavailable drugs that are effective against acute and latent toxoplasmosis, likely acting as inhibitors of the Q(i) site of the T. gondii cytochrome bc(1) complex.